1. Field of the Invention
This invention relates to a process for preparing ondansetron hydrochloride dihydrate having a defined particle size. The prepared ondansetron hydrochloride dihydrate is suitable for homogeneous distribution in a tablet blend.
2. Description of Related Art
Ondansetron (1,2,3,9-tetrahydro-9-methyl-3-[(2-methyl-1H-imidazol-1-yl)methyl]-4H-carbazol-4-one) selectively blocks the serotonin 5-HT3 receptor type. Ondansetron is marketed for the treatment of nausea under the tradename ZOFRAN® (GlaxoSmithKline, Research Triangle Park, N.C.). Ondansetron has the following chemical structure:

Ondansetron exists both in free base and hydrochloride dihydrate salt forms. Ondansetron hydrochloride dihydrate salt is the form used in tablet formulations. In tablet formulations, the particle size of the ondansetron hydrochloride dihydrate is critical. Because only a low dose of drug substance (i.e., ondansetron) per tablet is required, uniform tablets can only be prepared if the ondansetron hydrochloride dihydrate has a uniformly small particle size, which permits homogeneous distribution in a tablet blend (e.g., at least about 70% of the particles are smaller than 250 μm).
U.S. Pat. No. 4,695,578 ('578 patent) discloses a process for preparing ondansetron hydrochloride dihydrate having a large particle size (e.g., less than about 60% of the particles are smaller than 250 μm). The '578 patent process involves the step of cooling a solution of ondansetron hydrochloride, isopropanol, and water, optionally followed by an additional step of recrystallizing from a mixture of water and isopropanol.
A drawback of this process is that the obtained ondansetron hydrochloride dihydrate particles are too large to be homogeneously distributed in a tablet blend. Therefore, the ondansetron hydrochloride dihydrate particles described in the '578 patent cannot be used to make ondansetron hydrochloride dihydrate tablets having an acceptable uniform drug content.
As such, the particle size of the ondansetron hydrochloride dihydrate must further be reduced prior to formulation into tablets. However, conventional techniques for reducing particle size have proven to be unsuccessfull when applied to ondansetron hydrochloride dihydrate. For example, comminution milling of ondansetron hydrochloride dihydrate causes screen blockage of coarse and fine screens. Furthermore, although ondansetron hydrochloride dihydrate having a particle size of less than 250 μm can be obtained by passing the substance through a 60 mesh sieve (See UK Patent No. 2153821B), this method is not commercially viable.
U.S. Pat. No. 5,722,720 (the '720 patent) discloses a non-conventional technique for reducing particle size. In particular, the '720 patent discloses a multistep process in which ondansetron hydrochloride dihydrate is first dried at elevated temperature and reduced or atmospheric pressure, and is then cooled to ambient temperature. The process requires the heating step to be performed until the ondansetron hydrochloride dihydrate is desolvated, and requires the cooling step to be performed until the ondansetron hydrochloride is rehydrated to form ondansetron hydrochloride dihydrate.
The '720 patent process has several disadvantages. First, the '720 patent process requires a prolonged time period (i.e., 16–24 hours) for the drying/desolvating step, plus an additional prolonged time period for the cooling/rehydrating step. Second, the '720 patent process requires vigorous and carefully controlled drying conditions. For example, when the drying step is performed at 48–52° C., a reduced pressure of 100–200 torr is required. When the drying step is performed at ambient pressure, an elevated temperature of 100° C. is required.
There is a continuing need for a process for preparing ondansetron hydrochloride dihydrate having a defined particle size that is suitable for preparing ondansetron hydrochloride dihydrate tablets.